Objectives: To assess the risk of lymphoproliferative disease or other malignancy (standardised incidence ratios (SIRs)), in patients with primary Sjogren’s syndrome according to the American-European Consensus Criteria (AECC), compared with patients with sicca syndrome (non-AECC) and the background population. To identify predictors of malignancy and describe lymphoma types and survival probabilities . Methods: A linked register study using information from the Malmo Primary SS Register, Swedish Cancer Register, and Cause-of-Death Register for calculation of SIRs was carried out. Detected lymphomas were reclassified according to the WHO classification. Cox regression analysis was used to study the predictive value of clinical, laboratory, and histological findings at the time of diagnosis. Results: 507 patients with a median follow up of 8 years (range 1 month to 19 years) were included. SIRs (95% confidence interval (CI)) for malignancies in total and for non-Hodgkin’s lymphomas (NHL) were 1.42 (0.98 to 2.00) and 15.57 (7.77 to 27.85), respectively, in those fulfilling the AECC (n = 286). In non-AECC sicca patients (n = 221) SIR for malignancy of any kind was 0.77 (0.41 to 1.32); no lymphoproliferative neoplasms were detected. Significant predictors of lymphoproliferative disease were purpura/skin vasculitis (hazard ratio (HR) = 4.64, 95% CI 1.13 to 16.45), low complement factor C3 (HR = 6.18, 95% CI 1.57 to 24.22), low C4 (HR = 9.49, 95% CI 1.94 to 46.54), CD4+ T lymphocytopenia (HR = 8.14, 95% CI 2.10 to 31.53), and a low CD4+/CD8+ T cell ratio ⩽0.8 (HR = 10.92, 95% CI 2.80 to 41.83). 7/12 (58%) NHLs were diffuse large B cell lymphomas. Conclusion: A 16-fold increased risk for development of NHL was found. CD4+ T lymphocytopenia is an additional strong risk factor for developing lymphoma.

/pdf/lymphoma-and-other-malignancies-in-primary-sjogren-s-4rwt6to0cl.pdf

Lymphoma and other malignancies in primary sjogren's syndrome A cohort study on cancer incidence and lymphoma predictors.

Saliva in health and disease: an appraisal and update.

Objective: To identify drugs associated with the complaint of dry mouth.

Materials and Methods: MEDLINE was searched for papers 1980–2002 using keywords, oral, mouth, salivary, drugs, dry mouth and xerostomia, and relevant secondary references were hand-searched.

Results: Evidence was forthcoming for a number of xerogenic drugs, especially antimuscarinic agents, some sympathomimetic agents, and agents affecting serotonin and noradrenaline uptake, as well as a miscellany of other drugs such as appetite suppressants, protease inhibitors and cytokines.

Conclusion: Dry mouth has a variety of possible causes but drugs – especially those with anticholinergic activity against the M3 muscarinic receptor – are the most common cause of reduced salivation.

https://onlinelibrary.wiley.com/doi/pdf/10.1034/j.1601-0825.2003.03967.x

Drug effects on salivary glands: dry mouth

Salivary gland disease gives rise to salivary gland enlargement, pain, and prolonged xerostomia (dry mouth). Xerostomia is the most common long-standing problem for the majority of affected patients. There are many causes of dry mouth, with long-standing xerostomia being a particular problem in Sjogren's syndrome and after radiation to the head and neck region. Xerostomia is usually managed with saliva substitutes, but a large number of potential systemic therapies of long-standing xerostomia now exist. Some-particularly immunosuppressants-are of fundamental interest for the potential reduction of gland damage in Sjogren's syndrome but as yet are of limited clinical usefulness. Others, particularly pilocarpine and cevimeline, are, or have the potential to be, clinically useful in stimulating salivation by virtue of their action on cholinergic receptors.

https://exodontia.info/files/Oral_Medicine_Oral_Surgery_Oral_Pathology_-_An_update_of_the_etiology_and_management_of_xerostomia.pdf

An update of the etiology and management of xerostomia

Sjogren’s syndrome (SS), which was first described in 1933 by the Swedish physician Henrik Sjogren (1), is a chronic autoimmune disorder clinically characterized by a dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca). The disease primarily affects women, with a ratio of 9:1 over the occurrence in men. While SS affects up to 4 million Americans, about half of the cases are primary SS. Primary SS occurs alone, whereas secondary SS presents in connection with another autoimmune disease, such as rheumatoid arthritis or systemic lupus erythematosus (SLE). Histologically, SS is characterized by infiltration of exocrine gland tissues by predominantly CD4 T lymphocytes. At the molecular level, glandular epithelial cells express high levels of HLA–DR, which has led to the speculation that these cells are presenting antigen (viral antigen or autoantigen) to the invading T cells. Cytokine production follows, with interferon (IFN) and interleukin-2 (IL-2) being especially important. There is also evidence of B cell activation with autoantibody production and an increase in B cell malignancy. SS patients exhibit a 40-fold increased risk of developing lymphoma.

SS is a complex disease that can go undiagnosed for several months to years. Although the underlying immune-mediated glandular destruction is thought to develop slowly over several years, a long delay from the start of symptoms to the final diagnosis has been frequently reported. SS presumably involves the interplay of genetic and environmental factors. To date, few of these factors are well understood. As a result, there is a lack of early diagnostic markers, and diagnosis usually lags symptom onset by years. A new international consensus for the diagnosis of SS requires objective signs and symptoms of dryness, including a characteristic appearance of a biopsy sample from a minor or major salivary gland and/or the presence of autoantibody such as anti-SSA (2–4). However, establishing the diagnosis of primary SS has been difficult in light of its nonspecific symptoms (dry eyes and mouth) and the lack of both sensitive and specific biomarkers, either body fluid– or tissue-based, for its detection. It is widely believed that developing molecular biomarkers for the early diagnosis of primary SS will improve the application of systematic therapies and the setting of criteria with which to monitor therapies and assess prognosis (e.g., lymphoma development).

Saliva is the product of 3 pairs of major salivary glands (the parotid, submandibular, and sublingual glands) and multiple minor salivary glands that lie beneath the oral mucosa. Human saliva contains many informative proteins that can be used for the detection of diseases. Saliva is an attractive diagnostic fluid because testing of saliva provides several key advantages, including low cost, noninvasiveness, and easy sample collection and processing. This biologic fluid has been used for the survey of general health and for the diagnosis of diseases in humans, such as human immunodeficiency virus, periodontal diseases, and autoimmune diseases (5–8). Our laboratory is active in the comprehensive analysis of the saliva proteome (for more information, see www.hspp.ucla.edu), thus providing the technologies and expertise to contrast proteomic constituents in primary SS with those in control saliva (9–11). Thus far, we have identified over 1,000 proteins in whole saliva (WS). In addition, we have recently identified and cataloged ~3,000 messenger RNAs (mRNA) in human WS (12). These studies have provided a solid foundation for the discovery of biomarkers in the saliva of patients with primary SS. We have previously demonstrated proteome- and genome-wide approaches to harnessing saliva protein and mRNA signatures for the detection of oral cancer in humans (13,14).

There have been continuous efforts in the search for biomarkers in human serum or saliva for the diagnosis of primary SS. Some gene products were found at elevated levels in SS patient sera or saliva, including β2-microglobulin (β2m), soluble IL-2 receptor, IL-6, anti-Ro/SSA, anti-La/SSB, and anti–α-fodrin autoantibodies (15–20). However, none of them individually is sensitive or specific enough to use for the confirmative diagnosis of SS (15). Therefore, it is crucial to use emerging proteome- and genome-wide approaches to discover a wide spectrum of informative and discriminatory biomarkers that can be combined to improve the sensitivity and specificity for the detection of primary SS.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.22954

Salivary proteomic and genomic biomarkers for primary sjögren's syndrome

A series of different ultrasonographic abnormalities detected by salivary gland echography (SGE) were investigated for their discriminant power for Sjogren's syndrome (SS) in 53 patients with either primary SS (n = 27) or secondary SS (n = 26), as well as in 90 controls. Among the controls, 26 suffered from dry mouth and/or recurrent or persistent swelling of at least one parotid or submandibular gland due to other selected disorders, while 64 were healthy, asymptomatic subjects. Mild, evident or gross inhomogeneous parenchymal patterns were the only variables selected by stepwise discriminant analysis, when comparing patients to controls. However, a mild submandibular inhomogeneity did not prove useful for such a discrimination. Based on these data, a simplified evaluation and standardised quantification of salivary involvement, as detected by SGE, is proposed using an echographic score (range 0 to 6) which assigns points to the different degrees of glandular inhomogeneity. Score values above 0 showed a sensitivity of 88.8% in primary SS and of 53.8% in secondary SS, as well as a specificity of 84.6% and of 92.2% with respect to either symptomatic or healthy controls. The lower sensitivity of SGE for patients with secondary SS presumably was a result of their milder salivary involvement.

Salivary gland echography in primary and secondary Sjögren's syndrome.

Objective. The effect of recombinant interferon alpha-2 (IFNα2) therapy in Sjogren's syndrome (SS) was studied. Methods. An open study was performed in which 20 SS patients were given IFNα2 3.10 6 MU/3 times/week or OH-chloroquine (OH-C) 6 mg/kg/daily, for a mean period of 11 months. Results. Gland assessment showed that lacrimal and salivary funcfion improved by 67% and 61% versus 15% and 18% respectively (p < 0.01) in the patients treated with IFNα2 compared to those treated with OH-C. Immunological parameters did not change over time in either group. In 3 patients a decrease in the tissue score was observed in the IFNα2 group, while no changes were seen in the control group. Tolerability was acceptable. Conclusion. This study shows that IFN can improve tear function and dry mouth in SS, without causing significant side effects.

Interferon alpha-2 (IFN alpha 2) increases lacrimal and salivary function in Sjögren's syndrome patients. Preliminary results of an open pilot trial versus OH-chloroquine.

Castleman's disease is an atypical lymphoproliferative disorder characterized by the prevalence of B CD5-positive cells in the marginal zone. Autoimmune manifestations have often been reported, but the association of Castleman's disease with systemic autoimmune syndromes has been rarely described. However, many authors stress the difficulties in distinguishing between connective tissue disease and Castleman's disease in most cases. To clarify this issue, we describe a patient and review the literature reports of all cases of Castleman's disease associated with a connective tissue disease. A 19-year old woman presented with autoimmune thyroiditis and polymyositis. Seven years after the onset she developed a systemic inflammatory flare and a burst of autoimmunity, followed by generalized lymphoadenopathy. A mediastinal lymph node biopsy led to the diagnosis of Castleman disease of mixed type. Chemotherapy was given, with rapid response of the lymphoproliferative disorder but persistence of the underlying autoimmune disorder. The plasma concentration of B-lymphocyte stimulator (BLyS) was high (13.3 ng/mL) at the diagnosis of Castleman's disease. It fell dramatically after chemotherapy (4.97 ng/mL), even though it remained just above the mean BLyS value found in healthy blood donors (3.37+/-0.78 ng/mL).Castleman's disease can present autoimmune traits. In our patient, Castleman's disease complicated the course of a connective tissue disorder several years after the onset. We hypothesize that chronic stimulation of B-cell clones, particularly CD5+, by BLyS could favor the development of both autoimmune diseases and a broad range of lymphoproliferative disorders (such as Castleman's disease). This is the first report of increased BLyS levels in a patient with Castleman's disease, supporting a possible pathogenetic role of BLyS in the development of an autoimmune disorder and of a B lymphoproliferative disorder years later.

Systemic connective tissue disease complicated by Castleman's disease: report of a case and review of the literature.

OBJECTIVES The aim of the present study is to provide information on clinical outcome of the patients affected by HCV-positive mixed cryoglobulinemia (MC) treated with PEG-IFN and Ribavirin for 6 or 12 months according to the HCV genotype. METHODS Eighty-six patients (42 women and 44 men) were enrolled in 8 Italian centres. All the patients had MC in the active phase of the disease. The patients received Peginterferon alfa-2b 1.5 mcg/kg/once a week (QW) and daily oral Ribavirin (800/1,000/1,200) according to their body weight for 48 weeks for genotype 1 and 4 and for 24 weeks for genotypes 2 and 3. RESULTS In the 44 patients who underwent 12 months of therapy, 17 cases (39%) could be considered as 'non-responders' and 11 relapsed, therefore only 16 patients (36%) obtained a sustained virological response. In the 42 patients who underwent six months of therapy only 7 cases (17%) could be considered as 'non-responders' and 8 relapsed, therefore 27 patients (64%) obtained a sustained virological response. Purpura score dropped in both group (p<5.79 x 10-17) and only 5 cases of the group A (11%) and 5 of the group B (12%) did not show any improvement. Arthralgias showed a similar behaviour. Many patients relapsed after the end of the treatment. CONCLUSIONS This study documents a lower response rate than that observed in the clinical trials with HCV chronic hepatitis, but the presence of comorbidities and older age should be taken into consideration. Most patients (88.5%) showed a complete and persistent recovery from clinical symptoms.

Efficacy and safety of peginterferon alfa-2b plus ribavirin for HCV-positive mixed cryoglobulinemia: a multicentre open-label study.

Background: Hepatis C virus infection is presently an exclusion criterion to classify Sjogren's syndrome; however, there are distinct clinicopathologic and biologic similarities between HCV-related and SS-related chronic inflammation of mucosa-associated lymphoid tissue and lymphoproliferation that suggest common pathogenetic pathways. Objectives: To determine whether a subset of patients with sicca syndrome and HCV infection may present a true primary SS rather than a distinct clinicobiologic entity. Methods: We extensively characterized 20 consecutive patients with positive anti-HCV antibodies and heavy subjective dry eye and/or dry mouth symptoms, plus positive unstimulated sialometry and/or Shirmer's test. We then compared these features with those in HCV-negative primary SS controls (classified according to the latest American-European Consensus Group Classification Criteria for SS). Results: Of the 20 HCV-positive patients with sicca manifestations, 12 (60%) had positive anti-SSA/SSB antibodies (3/12 by enzyme-linked immunosorbent assay and 6/12 by immunoblot) and/ or positive salivary gland biopsy (at least 1 focus/4 mm 2 ), which met the strict classification criteria for SS, as in the case of HCV-negative SS controls. Comparing the HCV-positive SS subset with HCV-negative SS controls showed similar female to male ratio (11/1 vs. 46/4), major salivary gland swelling (17% vs. 26%), positive antinuclear antibodies (75 vs. 94%) and positive rheumatoid factor (58 vs. 52%). Significant differences (P < 0.05) were seen in mean age (69 vs. 56 years), liver disease (50 vs. 2%), lung disease (25 vs. 0%), anti-SSA/SSB positivity (25 vs. 90%), and low C3 or C4 (83 vs. 36%). HCV-positive SS patients exhibited a trend for more frequent chronic gastritis (50 vs. 22%), fibromyalgia (33 vs. 14%), peripheral neuropathy (33 vs. 18%), purpura (33 vs. 19%) and cryoglobulinemia (33 vs. 6%). Conclusions: A major subset of HCV-positive patients with definite subjective sicca symptoms and positive objective tests may indeed present a true, though peculiar, subset of SS. There are strict similarities with key clinical, pathologic and immunologic findings of definite HCV-negative SS. Other features appear more characteristic of HCV infection. When also considering that HCV is sialotropic and may be treated, HCV-related chronic sialadenitis represents a unique opportunity to clarify key pathogenetic events occurring in the large majority of HCV-negative SS; and similarities to typical primary SS, rather than differences, should be taken into account.

De Vita S

Papers

Salivary gland echography in primary and secondary Sjögren's syndrome.

Interferon alpha-2 (IFN alpha 2) increases lacrimal and salivary function in Sjögren's syndrome patients. Preliminary results of an open pilot trial versus OH-chloroquine.

Systemic connective tissue disease complicated by Castleman's disease: report of a case and review of the literature.

Efficacy and safety of peginterferon alfa-2b plus ribavirin for HCV-positive mixed cryoglobulinemia: a multicentre open-label study.

True primary Sjögren's syndrome in a subset of patients with hepatitis C infection: a model linking chronic infection to chronic sialadenitis.